Postmortem Assessment of Olfactory Tissue Degeneration and Microvasculopathy in Patients With COVID-19 | Infectious Diseases | JN Learning | AMA Ed Hub [Skip to Content]
Outline
Claim CME
PDF
Coronavirus (COVID-19)

Postmortem Assessment of Olfactory Tissue Degeneration and Microvasculopathy in Patients With COVID-19

To identify the key insights or developments described in this article
1 Credit CME
JAMA Neurology
June 1, 2022
Original Investigation
Cheng-Ying Ho, MD, PhD1,2;
Mohammad Salimian, MD3;
Julia Hegert, MD3;
Jennifer O’Brien, BSc2;
Sun Gyeong Choi, BSc2;
Heather Ames, MD, PhD2;
Meaghan Morris, MD, PhD1;
John C. Papadimitriou, MD, PhD2;
Joseph Mininni, MD2;
Peter Niehaus, BSc1,2;
Allen Burke, MD2;
Leyla Canbeldek, MD2;
Jonathan Jacobs, MD2;
Autumn LaRocque, MD2;
Kavi Patel, MD2;
Kathryn Rice, MD2;
Ling Li, MD4;
Robert Johnson, MSc5,6;
Alexandra LeFevre, MSc5,6;
Thomas Blanchard, PhD5,6;
Ciara M. Shaver, MD, PhD7;
Ann Moyer, MD, PhD8;
Cinthia Drachenberg, MD2
Author Affiliations
  • 1Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
  • 2Department of Pathology, University of Maryland School of Medicine, Baltimore
  • 3Department of Pathology, Orlando Health, Orlando, Florida
  • 4Office of the Chief Medical Examiner, Baltimore, Maryland
  • 5University of Maryland Brain and Tissue Bank, Baltimore
  • 6Department of Pediatrics, University of Maryland School of Medicine, Baltimore
  • 7Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
  • 8Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
Read article on JAMA Network

MOC/CME Information

editorial comment icon
Editorial
Comment
 related articles icon
Related
Articles
 author interview icon
Interviews
 multimedia icon
Multimedia
Audio Author Interview (16:55)
Postmortem Assessment of Olfactory Tissue Degeneration and Microvasculopathy in Patients With COVID-19
Read Article Claim CME
Key Points

Question  What are the neuropathologic changes of COVID-19 in the olfactory region?

Findings  In this cohort study of 23 deceased patients with COVID-19 and 14 matched controls, more severe axon pathology, axon losses, and microvascular pathology were noted in olfactory tissue from patients with COVID-19 than that from the control individuals. The olfactory pathology was particularly severe in patients with reported smell alterations but were not associated with the clinical severity, timing of infection, or the presence of SARS-CoV-2 in the olfactory tissue.

Meaning  In the region of olfactory bulb and olfactory tract, COVID-19 infection was associated with axon pathology and microvasculopathy, particularly in patients with smell alterations; the olfactory pathology did not result from direct viral injury and may be associated with local inflammation.

Abstract

Importance  Loss of smell is an early and common presentation of COVID-19 infection. Although it has been speculated that viral infection of olfactory neurons may be the culprit, it is unclear whether viral infection causes injuries in the olfactory bulb region.

Objective  To characterize the olfactory pathology associated with COVID-19 infection in a postmortem study.

Design, Setting, and Participants  This multicenter postmortem cohort study was conducted from April 7, 2020, to September 11, 2021. Deceased patients with COVID-19 and control individuals were included in the cohort. One infant with congenital anomalies was excluded. Olfactory bulb and tract tissue was collected from deceased patients with COVID-19 and appropriate controls. Histopathology, electron microscopy, droplet digital polymerase chain reaction, and immunofluorescence/immunohistochemistry studies were performed. Data analysis was conducted from February 7 to October 19, 2021.

Main Outcomes and Measures  (1) Severity of degeneration, (2) losses of olfactory axons, and (3) severity of microvasculopathy in olfactory tissue.

Results  Olfactory tissue from 23 deceased patients with COVID-19 (median [IQR] age, 62 [49-69] years; 14 men [60.9%]) and 14 control individuals (median [IQR] age, 53.5 [33.25-65] years; 7 men [50%]) was included in the analysis. The mean (SD) axon pathology score (range, 1-3) was 1.921 (0.569) in patients with COVID-19 and 1.198 (0.208) in controls (P < .001), whereas axon density was 2.973 (0.963) × 104/mm2 in patients with COVID-19 and 3.867 (0.670) × 104/mm2 in controls (P = .002). Concomitant endothelial injury of the microvasculature was also noted in olfactory tissue. The mean (SD) microvasculopathy score (range, 1-3) was 1.907 (0.490) in patients with COVID-19 and 1.405 (0.233) in control individuals (P < .001). Both the axon and microvascular pathology was worse in patients with COVID-19 with smell alterations than those with intact smell (mean [SD] axon pathology score, 2.260 [0.457] vs 1.63 [0.426]; P = .002; mean [SD] microvasculopathy score, 2.154 [0.528] vs 1.694 [0.329]; P = .02) but was not associated with clinical severity, timing of infection, or presence of virus.

Conclusions and Relevance  This study found that COVID-19 infection is associated with axon injuries and microvasculopathy in olfactory tissue. The striking axonal pathology in some cases indicates that olfactory dysfunction in COVID-19 infection may be severe and permanent.

Sign in to take quiz and track your certificates

Buy This Activity

JN Learning™ is the home for CME and MOC from the JAMA Network. Search by specialty or US state and earn AMA PRA Category 1 CME Credit™ from articles, audio, Clinical Challenges and more. Learn more about CME/MOC

Related Articles

  1. Olfactory Dysfunction in Patients With Mild COVID-19 in Rio de Janeiro, Brazil

Related Multimedia

  1. Postmortem Assessment of Olfactory Tissue Degeneration and Microvasculopathy in Patients With COVID-19

CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.

See More About

Infectious Diseases Pathology and Laboratory Medicine Coronavirus (COVID-19)
Article Information

Accepted for Publication: January 13, 2022.

Published Online: April 11, 2022. doi:10.1001/jamaneurol.2022.0154

Corresponding Author: Cheng-Ying Ho, MD, PhD, Department of Pathology, Johns Hopkins University School of Medicine, 1800 Orleans St, Zayed M2101, Baltimore, MD 21287 (cho9@jh.edu).

Author Contributions: Dr Ho had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Ho, Papadimitriou, Mininni, Li.

Acquisition, analysis, or interpretation of data: Ho, Salimian, Hegert, O'Brien, Choi, Ames, Morris, Papadimitriou, Mininni, Niehaus, burke, Canbeldek, Jacobs, LaRocque, Patel, Rice, Johnson, LeFevre, Blanchard, Shaver, Moyer, Drachenberg.

Drafting of the manuscript: Ho, Hegert, Canbeldek.

Critical revision of the manuscript for important intellectual content: Ho, Salimian, O'Brien, Choi, Ames, Morris, Papadimitriou, Mininni, Niehaus, burke, Jacobs, LaRocque, Patel, Rice, Li, Johnson, LeFevre, Blanchard, Shaver, Moyer, Drachenberg.

Statistical analysis: Ho, Papadimitriou, Niehaus, Drachenberg.

Obtained funding: Ho.

Administrative, technical, or material support: Ho, Salimian, O'Brien, Ames, Papadimitriou, Mininni, burke, Jacobs, Rice, Li, Johnson, LeFevre, Blanchard, Shaver, Drachenberg.

Supervision: Ho, Shaver.

Conflict of Interest Disclosures: Dr Shaver reported grants from the National Institutes of Health during the conduct of the study. No other disclosures were reported.

Funding/Support: This study was supported by the National Institutes of Health (grant K08NS102468 to Dr Ho and grant 75N95019C00048-P00006-9999-1 to Dr Blanchard).

Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

References
1.
Agyeman  AA , Chin  KL , Landersdorfer  CB , Liew  D , Ofori-Asenso  R .  Smell and taste dysfunction in patients with COVID-19: a systematic review and meta-analysis.   Mayo Clin Proc. 2020;95(8):1621-1631. doi:10.1016/j.mayocp.2020.05.030PubMedGoogle ScholarCrossref
2.
Carignan  A , Valiquette  L , Grenier  C ,  et al.  Anosmia and dysgeusia associated with SARS-CoV-2 infection: an age-matched case-control study.   CMAJ. 2020;192(26):E702-E707. doi:10.1503/cmaj.200869Google ScholarCrossref
3.
Giacomelli  A , Pezzati  L , Conti  F ,  et al.  Self-reported olfactory and taste disorders in patients with severe acute respiratory coronavirus 2 infection: a cross-sectional study.   Clin Infect Dis. 2020;71(15):889-890. doi:10.1093/cid/ciaa330PubMedGoogle ScholarCrossref
4.
Moein  ST , Hashemian  SM , Tabarsi  P , Doty  RL .  Prevalence and reversibility of smell dysfunction measured psychophysically in a cohort of COVID-19 patients.   Int Forum Allergy Rhinol. 2020;10(10):1127-1135. doi:10.1002/alr.22680PubMedGoogle ScholarCrossref
5.
Moein  ST , Hashemian  SM , Mansourafshar  B , Khorram-Tousi  A , Tabarsi  P , Doty  RL .  Smell dysfunction: a biomarker for COVID-19.   Int Forum Allergy Rhinol. 2020;10(8):944-950. doi:10.1002/alr.22587PubMedGoogle ScholarCrossref
6.
Lechien  JR , Chiesa-Estomba  CM , Beckers  E ,  et al.  Prevalence and 6-month recovery of olfactory dysfunction: a multicentre study of 1363 COVID-19 patients.   J Intern Med. 2021;290(2):451-461. doi:10.1111/joim.13209Google ScholarCrossref
7.
Zahra  SA , Iddawela  S , Pillai  K , Choudhury  RY , Harky  A .  Can symptoms of anosmia and dysgeusia be diagnostic for COVID-19?   Brain Behav. 2020;10(11):e01839. doi:10.1002/brb3.1839PubMedGoogle ScholarCrossref
8.
Cho  RHW , To  ZWH , Yeung  ZWC ,  et al.  COVID-19 viral load in the severity of and recovery from olfactory and gustatory dysfunction.   Laryngoscope. 2020;130(11):2680-2685. doi:10.1002/lary.29056PubMedGoogle ScholarCrossref
9.
Sayin  İ , Yaşar  KK , Yazici  ZM .  Taste and smell impairment in COVID-19: an AAO-HNS anosmia reporting tool-based comparative study.   Otolaryngol Head Neck Surg. 2020;163(3):473-479. doi:10.1177/0194599820931820PubMedGoogle ScholarCrossref
10.
Xydakis  MS , Dehgani-Mobaraki  P , Holbrook  EH ,  et al.  Smell and taste dysfunction in patients with COVID-19.   Lancet Infect Dis. 2020;20(9):1015-1016. doi:10.1016/S1473-3099(20)30293-0PubMedGoogle ScholarCrossref
11.
Hopkins  C , Surda  P , Whitehead  E , Kumar  BN .  Early recovery following new onset anosmia during the COVID-19 pandemic: an observational cohort study.   J Otolaryngol Head Neck Surg. 2020;49(1):26. doi:10.1186/s40463-020-00423-8PubMedGoogle ScholarCrossref
12.
Renaud  M , Thibault  C , Le Normand  F ,  et al.  Clinical outcomes for patients with anosmia 1 year after COVID-19 diagnosis.   JAMA Netw Open. 2021;4(6):e2115352-e2115352. doi:10.1001/jamanetworkopen.2021.15352PubMedGoogle ScholarCrossref
13.
Aragão  MFVV , Leal  MC , Cartaxo Filho  OQ , Fonseca  TM , Valença  MM .  Anosmia in COVID-19 associated with injury to the olfactory bulbs evident on MRI.   AJNR Am J Neuroradiol. 2020;41(9):1703-1706. doi:10.3174/ajnr.A6675Google ScholarCrossref
14.
Eliezer  M , Hamel  AL , Houdart  E ,  et al.  Loss of smell in patients with COVID-19: MRI data reveal a transient edema of the olfactory clefts.   Neurology. 2020;95(23):e3145-e3152. doi:10.1212/WNL.0000000000010806Google ScholarCrossref
15.
Laurendon  T , Radulesco  T , Mugnier  J ,  et al.  Bilateral transient olfactory bulb edema during COVID-19-related anosmia.   Neurology. 2020;95(5):224-225. doi:10.1212/WNL.0000000000009850Google ScholarCrossref
16.
Meinhardt  J , Radke  J , Dittmayer  C ,  et al.  Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervous system entry in individuals with COVID-19.   Nat Neurosci. 2021;24(2):168-175. doi:10.1038/s41593-020-00758-5PubMedGoogle ScholarCrossref
17.
Bryche  B , St Albin  A , Murri  S ,  et al.  Massive transient damage of the olfactory epithelium associated with infection of sustentacular cells by SARS-CoV-2 in golden Syrian hamsters.   Brain Behav Immun. 2020;89:579-586. doi:10.1016/j.bbi.2020.06.032PubMedGoogle ScholarCrossref
18.
Sia  SF , Yan  LM , Chin  AWH ,  et al.  Pathogenesis and transmission of SARS-CoV-2 in golden hamsters.   Nature. 2020;583(7818):834-838. doi:10.1038/s41586-020-2342-5PubMedGoogle ScholarCrossref
19.
Khan  M , Yoo  SJ , Clijsters  M ,  et al.  Visualizing in deceased COVID-19 patients how SARS-CoV-2 attacks the respiratory and olfactory mucosae but spares the olfactory bulb.   Cell. 2021;184(24):5932-5949.e15. doi:10.1016/j.cell.2021.10.027PubMedGoogle ScholarCrossref
20.
Bilinska  K , Jakubowska  P , Von Bartheld  CS , Butowt  R .  Expression of the SARS-CoV-2 entry proteins, ACE2 and TMPRSS2, in cells of the olfactory epithelium: identification of cell types and trends with age.   ACS Chem Neurosci. 2020;11(11):1555-1562. doi:10.1021/acschemneuro.0c00210PubMedGoogle ScholarCrossref
21.
Brann  DH , Tsukahara  T , Weinreb  C ,  et al.  Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia.   Sci Adv. 2020;6(31):eabc5801. doi:10.1126/sciadv.abc5801PubMedGoogle ScholarCrossref
22.
Bilinska  K , Butowt  R .  Anosmia in COVID-19: a bumpy road to establishing a cellular mechanism.   ACS Chem Neurosci. 2020;11(15):2152-2155. doi:10.1021/acschemneuro.0c00406PubMedGoogle ScholarCrossref
23.
Solomon  IH , Normandin  E , Bhattacharyya  S ,  et al.  Neuropathological features of Covid-19.   N Engl J Med. 2020;383(10):989-992. doi:10.1056/NEJMc2019373PubMedGoogle ScholarCrossref
24.
Mukerji  SS , Solomon  IH .  What can we learn from brain autopsies in COVID-19?   Neurosci Lett. 2021;742:135528. doi:10.1016/j.neulet.2020.135528PubMedGoogle ScholarCrossref
25.
Landis  JR , Koch  GG .  An application of hierarchical kappa-type statistics in the assessment of majority agreement among multiple observers.   Biometrics. 1977;33(2):363-374. doi:10.2307/2529786PubMedGoogle ScholarCrossref
26.
Engelmann  S , Ruewe  M , Geis  S ,  et al.  Rapid and precise semi-automatic axon quantification in human peripheral nerves.   Sci Rep. 2020;10(1):1935. doi:10.1038/s41598-020-58917-4PubMedGoogle ScholarCrossref
27.
Varga  Z , Flammer  AJ , Steiger  P ,  et al.  Endothelial cell infection and endotheliitis in COVID-19.   Lancet. 2020;395(10234):1417-1418. doi:10.1016/S0140-6736(20)30937-5PubMedGoogle ScholarCrossref
28.
Jin  Y , Ji  W , Yang  H , Chen  S , Zhang  W , Duan  G .  Endothelial activation and dysfunction in COVID-19: from basic mechanisms to potential therapeutic approaches.   Signal Transduct Target Ther. 2020;5(1):293. doi:10.1038/s41392-020-00454-7PubMedGoogle ScholarCrossref
29.
Jafek  BW , Murrow  B , Michaels  R , Restrepo  D , Linschoten  M .  Biopsies of human olfactory epithelium.   Chem Senses. 2002;27(7):623-628. doi:10.1093/chemse/27.7.623PubMedGoogle ScholarCrossref
30.
Temmel  AFP , Quint  C , Schickinger-Fischer  B , Klimek  L , Stoller  E , Hummel  T .  Characteristics of olfactory disorders in relation to major causes of olfactory loss.   Arch Otolaryngol Head Neck Surg. 2002;128(6):635-641. doi:10.1001/archotol.128.6.635PubMedGoogle ScholarCrossref
31.
Moran  DT , Jafek  BW , Eller  PM , Rowley  JC  III .  Ultrastructural histopathology of human olfactory dysfunction.   Microsc Res Tech. 1992;23(2):103-110. doi:10.1002/jemt.1070230202PubMedGoogle ScholarCrossref
32.
Lee  M-H , Perl  DP , Nair  G ,  et al.  Microvascular injury in the brains of patients with Covid-19.   N Engl J Med. 2021;384(5):481-483. doi:10.1056/NEJMc2033369PubMedGoogle ScholarCrossref
33.
Chiu  A , Fischbein  N , Wintermark  M , Zaharchuk  G , Yun  PT , Zeineh  M .  COVID-19-induced anosmia associated with olfactory bulb atrophy.   Neuroradiology. 2021;63(1):147-148. doi:10.1007/s00234-020-02554-1PubMedGoogle ScholarCrossref
34.
Kandemirli  SG , Altundag  A , Yildirim  D , Tekcan Sanli  DE , Saatci  O .  Olfactory bulb MRI and paranasal sinus CT findings in persistent COVID-19 anosmia.   Acad Radiol. 2021;28(1):28-35. doi:10.1016/j.acra.2020.10.006PubMedGoogle ScholarCrossref
35.
Schwabenland  M , Salié  H , Tanevski  J ,  et al.  Deep spatial profiling of human COVID-19 brains reveals neuroinflammation with distinct microanatomical microglia-T-cell interactions.   Immunity. 2021;54(7):1594-1610.e11. doi:10.1016/j.immuni.2021.06.002PubMedGoogle ScholarCrossref
36.
Mazzatenta  A , Neri  G , D’Ardes  D ,  et al.  Smell and taste in severe CoViD-19: self-reported vs. testing.   Front Med (Lausanne). 2020;7:589409. doi:10.3389/fmed.2020.589409PubMedGoogle ScholarCrossref
Want full access to the AMA Ed Hub?
Become an AMA member now
After you sign up for AMA Membership, make sure you sign in or create a Physician account with the AMA in order to access all learning activities on the AMA Ed Hub
Buy this activity
Close
Want full access to the AMA Ed Hub?
Become an AMA member now
After you sign up for AMA Membership, make sure you sign in or create a Physician account with the AMA in order to access all learning activities on the AMA Ed Hub
Buy this activity
Close
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
Close

Name Your Search

Save Search
Privacy Policy|Terms of Use
Close
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Close

Lookup An Activity

or

Close

My Saved Searches

You currently have no searches saved.

Close

My Saved Courses

You currently have no courses saved.

Close
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
Close
Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue